OBJECTIVE To examine the role of NPY in the progesterone-induced LHRH release in vivo. Previously, we have shown that during the progesterone-induced LHRH release the pulse frequency of NPY release increased concomitantly with the increase in LHRH release in vivo in rhesus monkeys. However, whether NPY plays any critical role in the progesterone-induced LHRH release is unknown. This study examined the effect of an antisense oligo for human NPY mRNA on the progesterone-induced LHRH release in vivo using push-pull perfusion in 6 female ovariectomized monkeys. All monkeys were implanted with a silastic capsule containing estradiol-17_ 12 days prior to, and then were s.c. injected with 30 5g estradiol benzoate 24 h prior to push-pull perfusion. On the day of experiment, to induce the LHRH surge, monkeys were further s.c. injected with 2.5 mg progesterone or oil (control), designated as time zero. The NPY antisense oligo (10 5M) was infused for 10 h starting 2 h before progesterone. Perfusate samples were obtained 4 h before progesterone, during the entire NPY antisense oligo infusion period, and an additional 4 h after NPY antisense oligo perfusion. For a control, an oligo containing the same bases in a scrambled sequence was similarly examined. LHRH and NPY levels in perfusate samples, collected in 10-min fractions were measured by RIA. NPY antisense oligo infusion blocked the progesterone-induced increase in the pulse frequency of NPY release. Moreover, NPY antisense oligo infusion blocked the progesterone-induced increase in the pulse frequency and pulse amplitude of LHRH release. The scrambled oligo infusion did not result in any changes in either NPY release or LHRH release. These data suggest that NPY release in the S-ME appears to be important for the progesterone action in estrogen-primed rhesus monkeys. FUTURE DIRECTIONS We will increase the number of animals in this study. KEY WORDS progesterone, pulsatile NPY release, LHRH surge, antisense NPY mRNA. FUNDING NIH HD15433 & RR00167